The major objective of this proposal is to further define how crystal-cell interactions which mediate gouty inflammation are regulated. The adhesive platelet membrane glycoprotein GpIIb- IIIa, a member of a widely distributed family of heterodimeric "cytoadhesins", directly modulates secretion in response to urate crystals. Crystal surface-bound LDL,via apolipoprotein B-100, suppresses cell stimulation by inhibiting physical crystal-cell association, and directly diminishes soluble GpIIb-IIIa binding to urate crystals. We propose to: 1) Test the biologic relevance of the in vitro inhibitory effects of LDL on crystal-cell interaction in an animal model of urate crystal-induced synovial inflammation in rabbits; 2) Define the epitopes on platelet GpIIb-IIIa mediating binding to urate crystals, using purified, solubilized GpIIb-IIIa and a panel of monoclonal GpIIb-IIIa-specific antibodies. Fab fragments of inhibitory antibodies will be prepared and we will evaluate their effects, and the effects of synthetic peptides constructed from deduced sequences of their epitopes, on platelet secretion induced by urate crystals; 3) Define by similar means to the above, the domains of apo B-100 mediating both LDL binding to urate crystals and the inhibitory effect of LDL on crystal- induced cell stimulation; 4) Compare the LDL isolated from acute gouty fluids vs. noninflammatory osteoarthritic fluids for the ability to suppress urate crystal-induced cell stimulation. In addition we will define the physical, biochemical and relevant functional properties of synovial fluid apo E, as apo E appears to share the inhibitory activity of apo B in vitro. Results of these studies will enhance understanding of crystal- induces inflammation. Definition of the structural bases for direct adhesion of GpIIb-IIIa to crystal surfaces, and the inhibitory effect of apo B-100 on inflammatory cell adhesion to certain surfaces, may lead to novel therapeutic approaches for particulate-induced inflammation.